We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

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The constitutively active JAK2 V617F mutant is the major determinant of human myeloproliferative neoplasms (MPNs). We show that coexpression of murine JAK2 V617F and the murine thrombopoietin (Tpo) receptor (TpoR, c-MPL) in hematopoietic cell lines or heterozygous knock-in of JAK2 V617F in mice leads to downmodulation of TpoR levels. Enhanced TpoR ubiquitinylation, proteasomal degradation, reduced recycling, and maturation are induced by the constitutive JAK2 V617F activity. These effects can be prevented in cell lines by JAK2 and proteasome inhibitors. Restoration of TpoR levels by inhibitors could be detected in platelets from JAK2 inhibitor-treated myelofibrosis patients that express the JAK2 V617F mutant, and in platelets from JAK2 V617F knock-in mice that were treated in vivo with JAK2 or proteasome inhibitors. In addition, we show that Tpo can induce both proliferative and antiproliferative effects via TpoR at low and high JAK2 activation levels, respectively, or on expression of JAK2 V617F. The antiproliferative signaling and receptor down-modulation by JAK2 V617F were dependent on signaling via TpoR cytosolic tyrosine 626. We propose that selection against TpoR antiproliferative signaling occurs by TpoR down-modulation and that restoration of down-modulated TpoR levels could become a biomarker for the treatment of IntroductionThe thrombopoietin (Tpo) receptor (c-MPL/TpoR) is crucial for megakaryocyte differentiation, platelet formation, and hematopoietic stem cell homeostasis. [1][2][3][4][5][6] TpoR signaling relies mainly on Janus kinase 2 (JAK2), 7-11 which also regulates traffic of the erythropoietin receptor (EpoR) and TpoR. 10,12 On Tpo binding to TpoR, JAK2 becomes activated and phosphorylates cytosolic TpoR tyrosine residues, which attract signaling molecules that activate signaling via STAT3/5, MAPK, and PI3K pathways. 7,[13][14][15][16][17] After activation, the receptor is internalized and then degraded by the proteasome and lysosome pathways, but also a substantial fraction is recycled back to the cell surface. 10,[18][19][20] Myeloproliferative neoplasms (MPNs) are malignant conditions arising from hematopoietic stem cells (HSCs) harboring molecular defects that promote excessive and cytokine-independent formation of mature myeloid blood cells. The unique somatic acquired JAK2 V617F mutation is shared by more than 95% of polycythemia vera and more than 50% of essential thrombocythemia patients. [21][22][23][24] The pseudokinase domain V617F mutation constitutively activates signaling, 21 via formation of active complexes with receptors, such as EpoR and TpoR.A seminal observation was represented by the post-translational down-regulation and impaired maturation of TpoR (c-MPL) in megakaryocytes and platelets of patients with MPNs. [25][26][27] In contrast, JAK2 strongly enhances maturation and stability of the cell-surface mature form of TpoR. 10 Here we asked whether JAK2 V617F can influence the traffic, maturation, and stability of TpoR, in cell lines, in JAK2 V617F knock-in mice, and in M...